U.S. patent number 4,393,041 [Application Number 06/143,709] was granted by the patent office on 1983-07-12 for fibrin binder/carrier for active biochemical agents.
This patent grant is currently assigned to International Minerals & Chemical Corp.. Invention is credited to David R. Bright, Ross G. Brown, Robert D. Williams.
United States Patent |
4,393,041 |
Brown , et al. |
July 12, 1983 |
Fibrin binder/carrier for active biochemical agents
Abstract
An adsorbable fibrin excipient for active biochemical agents
which enables controlled release of the biochemical agents when a
fibrin pellet or other article containing the biochemical agent is
implanted in an animal. Also contemplated are formable combinations
of fibrin and other materials, such as lactose, to vary the
absorption rate from the rate obtained using fibrin alone.
Inventors: |
Brown; Ross G. (Terre Haute,
IN), Bright; David R. (Terre Haute, IN), Williams; Robert
D. (Terre Haute, IN) |
Assignee: |
International Minerals &
Chemical Corp. (Terre Haute, IN)
International Minerals & Chemical Corp. (Terre Haute,
IN)
|
Family
ID: |
22505245 |
Appl.
No.: |
06/143,709 |
Filed: |
April 25, 1980 |
Current U.S.
Class: |
424/426 |
Current CPC
Class: |
A61K
9/2063 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 009/24 () |
Field of
Search: |
;424/19 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Lammert; Steven R. Barnett; H. J.
Lammert; Steven R. Barnett; H. J.
Claims
We claim:
1. In a method of administering an active biochemical agent to a
living animal over a controlled period of time by subcutaneously
implanting in said animal a pellet comprising said active
biochemical agent and a biocompatible excipient comprising bovine
fibrin, said active biochemical agent being selected from the group
consisting of hormones, steroids, estradiol compounds and anabolic
agents for promoting growth and feed efficiency in said living
animal.
2. In a method of administering an active biochemical agent to a
living animal over a controlled period of time by subcutaneously
implanting in said animal a pellet comprising said biochemical
agent and a biocompatible excipient, the improvement comprising
employing a pellet which comprises: 50-80% by weight zeranol;
10-30% by weight bovine fibrin; 0-10% by weight calcium sulfate;
0-10% by weight dextrin; 1-4% by weight boric acid; and 0.5-2% by
weight magnesium stearate, said pellet having a Strong-Cobb
Hardness Units value in the range of 3-10.
3. The method of claim 1, in which the pellet also comprises an
additional biocompatible excipient selected from the group
consisting of lactose, collagen, cholesterol, methylcellulose, PEG,
PPG, PVP, DBP, beeswax, carbowax, polylactides, magnesium stearate,
zinc stearate, starch-sugar mixtures, and combinations of
these.
4. In a solid, implantable pellet which includes a biocompatible
excipient and an active biochemical agent to be administered to an
animal over an extended period of time by subcutaneously implanting
the pellet in the animal, said biocompatible excipient comprising
bovine fibrin.
5. An implantable pellet comprising: 50-80% by weight zeranol;
10-30% by weight bovine fibrin; 0-10% by weight calcium sulfate;
0-10% by weight dextrin; 1-4% by weight boric acid; and 0.5-2% by
weight magnesium stearate, said pellet having a Strong-Cobb
Hardness Units value in the range of 3-10.
6. In a biocompatible pelletized controlled release system for an
active biochemical agent adapted for subcutaneous implant in a
living animal for release of said agent at a controlled release
rate into the living animal over a period of time, said release
system including a biocompatible excipient comprising 10-90% bovine
fibrin in combination with an active biochemical agent compressed
into a pellet having a hardness in the range of 3-10 Strong-Cobb
Hardness Units, said active biochemical agent being selected from
the group consisting of hormones, steroids, extradiol compounds and
anabolic agents for promoting growth and feed efficiency in said
living animal.
7. The controlled release system of claim 6, including an
additional biocompatible excipient to modify the rate of controlled
release characteristic of the fibrin, said additional biocompatible
material being selected from the group consisting of lactose,
collagen, cholesterol, methylcellulose, PEG, PPG, PVP, DBP,
beeswax, carbowax, polylactides, magnesium stearate, zinc stearate,
starch-sugar mixtures, and combinations of these.
Description
BACKGROUND OF THE INVENTION
This invention relates to absorbable implants for delivering a
biochemical agent into the system of an animal in a sustained
release over a period of time. Various biochemical agents are
conveniently administered to animals by means of subcutaneous
implants of pellets which comprise the active biochemical agent and
a biocompatible, absorbable excipient. Such biochemical agents
which have been administered by means of subcutaneous implants
include hormones and anabolic agents for improving growth and feed
efficiency in cattle, sheep, pigs and fowl. It is also contemplated
that various biochemical agents requiring sustained release can be
implanted in horses, dogs, cats, other domestic animals, zoo
animals and, in some situations, in wild animal populations.
Controlled release of certain hormones can be used to control
ovulation in cattle and sheep to schedule breeding programs.
Subcutaneous implanting is advantageous over ad libitum feeding of
many biochemical agents because it ensures that a sustained
effective dosage of the active biochemical agent is administered to
each animal. It is convenient to implant animals such as cattle and
sheep on the ear because the pellet is less likely to be dislodged
by the animal, and the ear can be discarded when the animal is
marketed.
The excipient used in the implant pellet is an important factor in
the physiological effect obtained. It should be biocompatible, and
nonirritating and dissolve completely without encapsulation to
release the active biochemical agent at the desired release
rate.
Lactose has long been used as an excipient for implant pellets, and
in tablets and pills. Lactose is relatively tasteless, and it is
biocompatible. Lactose excipients have been used to administer
anabolic agents, such as are described in U.S. Pat. No. 3,196,019
issued July 20, 1965. The active ingredient and the lactose are
blended together and pelleted into small spheres or cylindrical
shapes containing the desired dosage. Pelleting is conveniently
performed on a rotary tableting machine having the appropriate die
inserts. The Model B-2 Stokes rotary tableting machine has been
used for this purpose to produce pellets having a hardness in the
range of 5-10 Strong-Cobb Hardness Units (SCHU).
An implant formulation having a carrier comprising beeswax, zinc
stearate, dibutylphthalate (DBP) and polyvinylpyrrolidone (PVP) is
described in U.S. Pat. No. 3,428,729. The "DMP" compound is said to
be the key to slow the melting of the beeswax and "PVP" and,
therefore, to the controlled release of the active ingredient (a
hormone to regulate ovulation).
U.S. Pat. No. 3,499,445 is also directed to ovulation control by
subcutaneous implant, and describes a 3-layered compressed disc
implant pellet which contains chloesterol, carbowax and magnesium
stearate as the carrier material for certain steroid compounds. The
object again is to obtain a sustained release of the active steroid
compound from the composite disc implant. This patent also
discloses surgical removal of the implants after 14-18 days to
abruptly terminate the treatment.
A polylactide carrier/binder for use in combination with drugs in
the form of an implant is described in U.S. Pat. No. 3,773,919
issued Nov. 20, 1973 (See U.S. Pat. No. 3,773,919, column 9, line
59). The term "polylactide" includes a polyester derived from an
.alpha.-hydroxycarboxylic acid and more specifically, the polymer
derived from lactic acid (.alpha.-hydroxypropionic acid). The above
carrier material is said to undergo biodegradation in the body into
normal metabolic products.
An extensive discussion of various types of implant pellets is
found in U.S. Pat. No. 4,180,560 issued Dec. 25, 1979. This patent
is directed to a biocompatible, inert core implant having a
biosoluble coating comprising a carrier such as polyethylene glycol
(PEG) and cholesterol. The inert core materials listed include
glass, cellulose acetate, methylmethacrylate, other acrylics,
nylon, polypropylene, silicone rubber, PEG and sugar-starch
beads.
A fibrin prosthesis useful in surgical procedures is described in
U.S. Pat. No. 3,523,807 issued Aug. 11, 1970. The fibrin was
obtained from blood plasma by natural clotting through the addition
of calcium chloride solution. The clotted plasma was ground and the
serum pressed out, and the ground product is washed and dried to
provide a fibrin powder. The fibrin powder can be molded into
various shapes to be used in surgical procedures such as to
strengthen liver-sutures, provide a temporary cap for use in a
hip-joint operation and to elevate the urethra in a urogenital
surgical procedure.
Bovine fibrin is disclosed as being used for these surgical
purposes by Capperauld, et al., Properties of Bovine Fibrin
Absorbable Implants, Surgery, Gynecology and Obstetrics, Volume
144, pages 3-7 (January 1977). A method of making the fibrin is
disclosed which utilizes bovine plasma by first precipitating
fibrinogen with ethanol at a low temperature, following a
fractional precipitation procedure. The fibrinogen is redissolved
and converted into a stabilized fibrin clot by adding calcium
chloride. The clot is then minced, washed, purified, pulverized and
dried at 150.degree. C. to produce a bovine fibrin powder for the
surgical uses described.
SUMMARY
The subject invention utilizes bovine fibrin as biocompatible,
absorbable excipient for active biochemical agents which are first
mixed together and then formed into spherical or cylindrical
pellets suitable for subcutaneous implanting in an animal to be
treated. Biochemical agents which may be administered by this
method to obtain a sustained release over an extended period of
time include anabolic agents such as zeranol and hormones such as
estradiol compounds, also used to increase growth and feed
efficiency in animals.
DETAILED DESCRIPTION
The following examples illustrate how the invention may be
practiced to advantage.
EXAMPLE 1
Tests were made on three castrated male Angus/Hereford calves to
observe the absorption characteristics of pellets made with fibrin
excipient. The fibrin used for this test was obtained from Novex,
Limited, Budapest, Hungary (hereinafter referred to as "NOVEX"
fibrin).
The experimental fibrin-containing pellets used in the tests
described herein had the following constituents in the amounts
listed below:
______________________________________ Experimental Pellets
Ingredient Amount (mg) ______________________________________
Zeranol 12 Fibrin 3.35 Boric acid 0.55 Magnesium stearate 0.40 FD
& C Yellow .0065 16.31 Total
______________________________________
The above ingredients were thoroughly blended and then pelleted
using a cylindrical die insert in a Model B-2 Stokes Rotary
Tableting Machine to form cylindrical pellets containing the above
ingredients in the above amounts. The pellets were approximately
0.090 inches in diameter and 0.13 inches in length. The hardness of
the pellets was in the range of 5-10 Strong-Cobb Hardness Units,
more particularly, about 5.78 SCHU.
Procedure
Three 12 mg dosage experimental pellets using the "NOVEX" fibrin
excipient of the subject invention were used to implant the right
ears of each of the three castrated male Angus/Hereford calves.
The implant sites were examined by incision sixty-five days after
the above implants were made. The pellets containing "NOVEX" fibrin
excipient had been completely absorbed. The fibrin excipient was
concluded to be completely biocompatible, and gave excellent
absorption of the active biochemical agent. It was concluded from
the above results that the fibrin excipient is readily absorbable,
and can be used as a suitable excipient for subcutaneous implant
pellets to administer active biochemical agents to animals.
EXAMPLE 2
The above results were further verified by a second test. Eighteen
Angus/Charolais calves were used consisting of fourteen castrated
male calves and four female calves. Fifteen of the above calves
were implanted in their right ears with three experimental 12 mg
pellets (36 mg/calf) containing zeranol and utilizing bovine fibrin
as the excipient made as described above. This particular bovine
fibrin was obtained from the Nutritional Biochemicals Division of
ICN Life Sciences Group, Cleveland, Ohio. The remaining three
calves were implanted on their right ears with three experimental
12 mg pellets (36 mg/calf) containing zeranol and utilizing fibrin
obtained from Novex Limited,, Budapest, Hungary. This latter
material is promoted for use in human surgical procedures. The test
calves were examined at 15, 30, 48, 65 and 75 days and the pellets
(if palpable) were removed from three calves at each examination
date and assayed.
The approximate absorption rate for the experimental pellets
containing bovine fibrin were as follows: 73% by weight absorbed at
fifteen days, 92% by weight absorbed at thirty days, and 100% by
weight had been absorbed by forty-eight days. No difference in
absorption rate was observed between the "NOVEX" fibrin and the
bovine fibrin (obtained from ICN).
It is contemplated that the absorption rate can be adjusted by
using formulas combining mixtures of fibrin and lactose, or other
materials such as methylcellulose, collagen, cholesterol, carbowax,
beeswax, dibutylphthalate (DBP), polyvinylpyrrolidone (PVP), zinc
stearate, polylactides including .alpha.-hydroxypropionic acid,
polyethylene glycol (PEG), polypropylene (PPG) and sugar-starch
combinations.
EXAMPLE 3
The pellets may also be made up in the following formula, and
formed into spherical pellets:
______________________________________ Fibrin-Containing Spherical
Pellets Ingredient Amount (mg)
______________________________________ Zeranol 12 Fibrin 2.89
Calcium sulfate 1.7 Dextrin 1.28 FD & C Yellow .01 Boric acid
0.57 Magnesium stearate 0.28 18.73 Total
______________________________________
The above ingredients are thoroughly blended, and then formed into
pellets on a Stokes Model B2 rotary tableting machine having die
inserts to make generally spherical pellets substantially 1/8-inch
(0.125") in diameter and about 0.108 inches in height. The above
spherical pellets have substantially the same dosage per pellet as
the above described cylindrical pellets, and it could be expected
that the dissolution rate would be slightly lower because of the
spherical shape of the pellet, but typical pellet hardness is lower
(3-6 SCHU), which tends to accelerate the dissolution rate. The two
effects cancel each other.
* * * * *